1. Field of the Invention
The present invention relates to cardioplegic solutions, to preservation solutions, and to methods for transplanting organs. More particularly, this invention relates to cardioplegic solutions for arresting an organ for transplantation, to preservation solutions for perfusing and storing an organ while awaiting implantation, and to methods for using the cardioplegic and preserving solutions during transplantation of an organ.
2. The Prior Art
A great deal of research progress has been made over the years in understanding cellular mechanisms, as well as developing new transplantation techniques for keeping organs viable not only during storage but also after reperfusion of these organs. As a result, organ transplantation, including heart transplantation, is an established elective operation. A significant factor limiting the clinical application of organ transplantation is the deviation of viability of the organ after removal from the donor.
At present, the two most frequently used methods for heart transplantation are simple hypothermic storage and continuous pulsatile perfusion. With simple hypothermic storage, the heart is arrested with a cardioplegic solution, then removed from the donor and cooled rapidly. This is usually achieved by a combination of cooling and a short period of perfusion to drop the heart temperature as quickly as possible to a temperature between 0.degree. C. and 4.degree. C. where it may be held up to about 6 hours. While cold storage enables organs to be transplanted, the time during which the organ is viable is short. Cold storage decreases the rate at which intracellular enzymes, essential cellular components necessary for organ viability, degrade but does not stop metabolism.
The second method of organ preservation which has undergone extensive investigation, continuous pulsatile perfusion, includes the following steps: (1) pulsatile flow, (2) hypothermia, (3) membrane oxygenation, and (4) a perfusate containing both albumin and lipids. Although being more technically complex and costly, the advantages to using continuous pulsatile perfusion over simple hypothermia include longer viability of the organ and viability testing prior to implantation.
The compositions of numerous cardioplegic and preservation solutions have been extensively studied. For example, the protective properties of three cardioplegic solutions were compared by Gali nanes et al. (M. Gali nanes, T. Murashita and D. J. Hearse (1991) The Journal of Heart and Lung Transplantation (11) 624-635, at low temperatures and short time periods. A comparison of cold preservation solutions was set forth in G. Tian et al. (1991) The Journal of Heart and Lung Transplantation (10) 975-985, where the cold preservation solutions limited the storage time of the organs.
A storage solution for preserving organs which can be used at temperatures from 0.degree. C. to 37.degree. C. but was limited in storage time was disclosed in U.S. Pat. No. 5,145,771 to Lemasters et al. The solution requires the use of the colloid, hydroxyethyl starch, for oncotic support against interstitial edema. In the present invention edema is not a problem because no oxygen-derived free radicals are available to injure the organ.
Preserving organs at between 0.degree. C. and 4.degree. C. results in damage to the organ during storage and upon reperfusion with a warm reperfusion solution. Injury to the organ occurs through the loss of endothelial cells due to dissolved oxygen in the reperfusion solution. Although some of the solutions of the prior art have been useful to extend the storage time of donor organs and lessen injury to the organ upon reperfusion, cell injury still occurs. Therefore, it is desirable to extend the viable organ life and improve the quality of the transplanted organ. Extending the organ viability allows sufficient time for compatibility testing of the donor and recipient and increased organ availability.
The recovery of cardiac function is also greatly influenced by the time lapse between removal from the donor and reperfusion as well as the efficacy of protective interventions used during that period. To overcome the deleterious effects of ischemia, techniques such as intermittent or continuous perfusion have been used. Finally, reperfusion itself, although necessary for the survival of the tissue, may initiate a series of events known as reperfusion induced injury, which, if occurring, limit the extent or rate of recovery, Thus, modification of the nature of reperfusion is desirable to improve the recovery of the ischemic/reperfused myocardium.
More particularly, as a result of the deprivation of circulation, and thus oxygen (i.e., ischemia) during transplantation, the sodium pump, which normally maintains the intracellular composition high in potassium, magnesium, and phosphate and low in sodium and chloride, ceases to function due to the lack of energy, resulting in an inflow of sodium and chloride into the cells, and an outflow of potassium and to a lesser extent magnesium from the cells. The result of these rapid changes in Na.sup.+ --H.sup.+ distribution in the cell is a net gain, not merely an exchange, of intracellular ions followed by water and a profound loss of potassium and magnesium resulting in damage to the organ. The protective effects of Na/H exchange inhibitors, including amiloride and its analogs in the reperfused myocardium has been studied by Moffat, et al. (M. P. Moffat and M. Karmazyn, (1993), J. Molec. Cell Cardiol (25), 959-971).
It is therefore the general object of the present invention to provide cardioplegic solutions for arresting organs intended for transplantation and preserving solutions for pulsating and storing organs while awaiting implantation each of which inhibits ion exchange, extends the vitality of the organ, and reduces damage to the cells.
Another object of the present invention is to provide a method for arresting and preserving organs which extend the maximum life of the organ during transplantation.
Yet another object of the present invention is to provide a method of transplanting organs in which storage of the organ may be carried out at room temperature for up to at least 24 hours without significant damage to the organ.
Other objects, features, and advantages of the invention will be apparent from the following details of the invention as more fully described.